Forsberg, Leah K.

ObjectiveMicrotubule‐associated protein tau (MAPT) mutations cause frontotemporal lobar degeneration, and novel biomarkers are urgently needed for early disease detection. We used task‐free functional magnetic resonance imaging (fMRI) mapping, a promising biomarker, to analyze network connectivity in symptomatic and presymptomatic MAPT mutation carriers.MethodsWe compared cross‐sectional fMRI data between 17 symptomatic and 39 presymptomatic carriers and 81 controls with (1) seed‐based analyses to examine connectivity within networks associated with the 4 most common MAPT‐associated clinical syndromes (ie, salience, corticobasal syndrome, progressive supranuclear palsy syndrome, and default mode networks) and (2) whole‐brain connectivity analyses. We applied K‐means clustering to explore connectivity heterogeneity in presymptomatic carriers at baseline. Neuropsychological measures, plasma neurofilament light chain, and gray matter volume were compared at baseline and longitudinally between the presymptomatic subgroups defined by their baseline whole‐brain connectivity profiles.ResultsSymptomatic and presymptomatic carriers had connectivity disruptions within MAPT‐syndromic networks. Compared to controls, presymptomatic carriers showed regions of connectivity alterations with age. Two presymptomatic subgroups were identified by clustering analysis, exhibiting predominantly either whole‐brain hypoconnectivity or hyperconnectivity at baseline. At baseline, these two presymptomatic subgroups did not differ in neuropsychological measures, although the hypoconnectivity subgroup had greater plasma neurofilament light chain levels than controls. Longitudinally, both subgroups showed visual memory decline (vs controls), yet the subgroup with baseline hypoconnectivity also had worsening verbal memory and neuropsychiatric symptoms, and extensive bilateral mesial temporal gray matter decline.InterpretationNetwork connectivity alterations arise as early as the presymptomatic phase. Future studies will determine whether presymptomatic carriers' baseline connectivity profiles predict symptomatic conversion. ANN NEUROL 2023;94:632–646

AbstractBackgroundThe ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study is designed to characterize both sporadic and familial FTLD (f‐FTLD) through annual detailed clinical, neuropsychological, biomarker, and neuroimaging assessments to capture disease onset and trajectory in preparation for therapeutic trails in FTLD. Transitions from asymptomatic to mild disease, or from mild to overt, may reveal critical windows for intervention.Method169 f‐FTLD participants carrying mutations in the main FTLD‐associated genes (79 C9orf72; 37 GRN; 53 MAPT) with at least two clinical assessments were included for analysis of phenoconversion from asymptomatic or mild disease. [CDRÒ + NACC FTLD global scores (Miyagawa et al, 2020) were used to define baseline status at first visit: “asymptomatic” = 0 and “mild” = 0.5. Conversion was defined as “partial” (asymptomatic to mild), “definite” (asymptomatic to overt [CDRÒ + NACC FTLD > = 1) and “mild to overt” (0.5 to > = 1).ResultDefinite conversion occurred most often in MAPT mutation carriers, with 5/43 asymptomatic carriers transitioning through mild to overt across multiple visits. Definite conversion was also seen in 2/65 C9orf72 expansion carriers and 1/30 GRN mutation carriers. All definite converters were assessed as mild (CDRÒ + NACC FTLD = 0.5) for at least one intermediate visit; definite conversion was observed from 2‐4 years from initial assessment. Partial conversions also occurred in all three genetic groups (MAPT: 6; C9orf72: 5; GRN: 5). Further conversion is expected to be observed in these participants in additional follow‐up visits. C9orf72 expansion carriers were less likely to progress from a baseline of mild to overt (3/14) than GRN carriers (4/6) or MAPT (7/10).ConclusionLongitudinal assessment through natural history studies can capture early phenoconversion in carriers of FTLD‐associated genetic mutations; corresponding imaging, cognitive, and biomarker profiles captured may provide insights into disease mechanisms and trajectories.

AbstractBackgroundThe ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) research consortium is actively enrolling participants across 23 North American centers to characterize sporadic and familial frontotemporal dementia (FTD) and prepare for disease‐modifying clinical trials. The ability to identify, otherwise unknown, relatives among these participants is critical to rigorously build family structures for downstream clinical and genetic research studies.MethodsGenome‐wide SNP genotyping data from ALLFTD participants was used to perform lineage analyses using PLINK. Briefly, QC was performed to remove individuals with low call rate and filter autosomal SNPs for missingness, allele frequency, and deviation from Hardy‐Weinberg equilibrium, before pruning SNPs for linkage disequilibrium. Identity‐by‐descent (IBD) estimates were then calculated for determining relatedness, followed by family‐network identification and pedigree reconstruction using PRIMUS.ResultsAbout 46% of ALLFTD participants that were genotyped and passed QC (n = 1,453) had reported a family history, while 50% (n = 721) did not and were considered sporadic. We identified a total of 460 participants that had at least one relative who was second degree or closer (PI_HAT>0.1875) based on IBD sharing, resulting in 150 family networks. This included 9 participants who self‐identified as sporadic, demonstrating the utility of direct genetic characterization to determine familiality in FTD. Most of the predicted families were associated with disease causing variants in the 3 major FTD‐causing genes: 66 families with known C9orf72 repeat expansion carriers, 35 with MAPT (including 11 families with the variant historically known as p.P301L) and 30 with GRN pathogenic variant carriers, as well as 2 families with carriers of both a C9orf72 expansion and a GRN pathogenic variant. We also identified 5 families with carriers of pathogenic variants in other familial dementia genes (2 TARDBP, 2 VCP and 1 PSEN1), as well as 12 families with yet unknown genetic etiology.ConclusionsThis dataset sets up a crucial resource to increase statistical accuracy and power in downstream association studies using the clinical, neuropsychological, neuroimaging and biomarker data currently being generated by the ALLFTD consortium. It will also facilitate genetic studies aimed at novel gene discovery, and identification of haplotypes and genetic modifiers associated with the 3 major FTD causal genes.

AbstractIntroductionRemote smartphone assessments of cognition, speech/language, and motor functioning in frontotemporal dementia (FTD) could enable decentralized clinical trials and improve access to research. We studied the feasibility and acceptability of remote smartphone data collection in FTD research using the ALLFTD Mobile App (ALLFTD‐mApp).MethodsA diagnostically mixed sample of 214 participants with FTD or from familial FTD kindreds (asymptomatic: CDR®+NACC‐FTLD = 0 [N = 101]; prodromal: 0.5 [N = 49]; symptomatic ≥1 [N = 51]; not measured [N = 13]) were asked to complete ALLFTD‐mApp tests on their smartphone three times within 12 days. They completed smartphone familiarity and participation experience surveys.ResultsIt was feasible for participants to complete the ALLFTD‐mApp on their own smartphones. Participants reported high smartphone familiarity, completed ∼ 70% of tasks, and considered the time commitment acceptable (98% of respondents). Greater disease severity was associated with poorer performance across several tests.DiscussionThese findings suggest that the ALLFTD‐mApp study protocol is feasible and acceptable for remote FTD research.HIGHLIGHTS The ALLFTD Mobile App is a smartphone‐based platform for remote, self‐administered data collection. The ALLFTD Mobile App consists of a comprehensive battery of surveys and tests of executive functioning, memory, speech and language, and motor abilities. Remote digital data collection using the ALLFTD Mobile App was feasible in a multicenter research consortium that studies FTD. Data was collected in healthy controls and participants with a range of diagnoses, particularly FTD spectrum disorders. Remote digital data collection was well accepted by participants with a variety of diagnoses.